Download - Sarcoidosis & orphan lung disease
Sarcoidosis & Sarcoidosis &
Orphan Lung Orphan Lung
DiseasesDiseases
Iman Galal , MDIman Galal , MDPulmonary Medicine DepartmentPulmonary Medicine Department
Ain Shams UniversityAin Shams University
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At The End Of This Lecture You Should Know
Who discovered Sarcoidosis?
Epidemiology of Sarcoidosis
Epidemiology of Sarcoidosis
Pathology of Sarcoidosis
Pathophysiology of Sarcoidosis
Organ involvement in Sarcoidosis
Staging of Sarcoidosis
How to diagnose Sarcoidosis?
How to treat Sarcoidosis?
Recommended clinical evaluation of Sarcoidosis
How to assess the activity of Sarcoidosis?
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Historical Perspective
In 1887, Sir Jonathan Hutchinson was the first to describe a case of cutaneous sarcoid disease. He named the condition "Mortimer's Malady" after the patient.
In 1899, Caesar Boeck called this condition 'sarcoid' as he thought it resembles sarcoma. It was called "Boeck's Sarcoid" in his honour.
Sir Jonathan Sir Jonathan HutchinsonHutchinson Caesar BoeckCaesar Boeck
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Epidemiology
Non-infectious multisystem granulomatous disorder of unknown origin.
Female > Male.
Black > White.
3rd & 4th decade with 2nd peak at 6th decade.
Prevalence rate: 10-40 cases per 100,000.
Mortality rate: 1-5 %.
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Etiology
Disease of unknown cause.
Possible infectious & transmissible cause in
genetically susceptible individuals.
Possible environmental exposure cause.
Possible genetic-environmental interactions.
Possible autoimmune cause.
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Pathophysiology of Sarcoidosis
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Pathophysiology of Sarcoidosis
T-helper cells to T-suppressor cells ratio is increased in BAL but decreased in peripheral blood.
Exaggerated T-cell activity indicates an altered immune response.
Hyper globulinemia (Ig A & Ig G).
Mass effect of granulomas damages the tissues.
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Pathology of Sarcoidosis
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Pathophysiology of Sarcoidosis
Non-caseating epithelioid cell granuloma is the characteristic lesion of sarcoidosis.
It occurs along perivascular, peribronchial & septal region areas rich in lymphatic vessels.
Granuloma consists of a central collection of modified mononuclear phagocytes called epithelioid cells.
Epithelioid cells are mature macrophages that gain secretory & bactericidal capabilities but lose some phagocytic capability.
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Pathophysiology of Sarcoidosis
Epithelioid cells are large, polygonal and have an elliptical nucleus which contains fine chromatin & 1-2 nucleoli.
Conglomeration of epithelioid cells with multiple peripherally arranged nuclei forms giant cells in the central part of the granuloma.
The central epithelioid & giant cells are surrounded by a rim of small, oval, basophilic T-lymphocytes.
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Pathology of Sarcoidosis
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Pathology of Sarcoidosis
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Inclusion Bodies in Sarcoidosis
Schaumann’s Bodies (Conchoidal Bodies) &
Birefringent Crystals:
Large, concentrically lamellated, calcified structures that are present within the cytoplasm of giant cells in 88% of cases of sarcoidosis.
The majority of Schaumann’s bodies have birefringent crystals composed of calcium oxalate.
Birefringent crystals may serve as a nidus for their formation.
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Pathology of Sarcoidosis
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Inclusion Bodies in Sarcoidosis
Asteroid Bodies:
Intracytoplasmic stellate inclusions within giant cells exhibiting 30 or more rays radiating from a central core.
They probably represent functionally obsolescent cell organelles.
Reported in 2 – 9 % of sarcoidosis.
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Inclusion Bodies in Sarcoidosis
Hamazaki-Wesenberg Bodies:
Also known as yellow-brown bodies, yellow bodies, spindle bodies & chromogenic bodies & giant extracellular & intracellular lysosomes.
Seen in lymph nodes.
They are 0.5 - 0.8 mm oval or spindle shaped, and often exhibit a yellow-brown color.
Because they may exhibit an appearance similar to yeast like budding they may be mistaken for fungal organisms.
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Pathology of Sarcoidosis
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Organ Involvement in Sarcoidosis
Organ System % of affection
Pulmonary > 90 %
Psychosocial 30-60 %
Ocular 20-30 %
Skin 20-30 %
Hematologic 20-30 %
Endocrine 10-30 %
Hepatic/Abdominal 10-20 %
Joints & Musculoskeletal
10-20 %
Exocrine gland 10-20 %
URT & Oral cavity 5-10 %
Cardiac 5-10 %
Neurological 5-10 %
Renal <5 %
Genitourinary <5 %
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Classification of Sarcoidosis
Asymptomatic (2/3 of patients).
Acute sarcoidosis ± erythema nodosum.
Intermediate sarcoidosis with symptoms or
signs of pulmonary disease for < 2 years.
Chronic pulmonary sarcoidosis of > 2 years.
Dominant extrapulmonary sarcoidosis.
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Pulmonary Sarcoidosis
Scadding's Classification
Stage 0=normal (5-15%)
Stage 1=Hilar LDN alone (45-65%)
Stage 2=Hilar LDN + parenchymal
infiltrates (30-40%)
Stage 3=Parenchymal infiltrates
alone (10-15%)
Stage 4=Pulmonary fibrosis (5%)
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Endobronchial Sarcoidosis
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Cutaneous Sarcoidosis
Erythema Erythema NodosumNodosum
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Lofgren's Syndrome
Bilateral hilar lymphadenopathy.
Fever.
Arthritis.
± Erythema nodosum.
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Cutaneous Sarcoidosis
Lupus PernioLupus Pernio
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Cutaneous Sarcoidosis
RAISED PLAQUESRAISED PLAQUES NODULAR LESIONSNODULAR LESIONS
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Ocular Sarcoidosis
Unilateral or bilateral anterior & posterior uveitis
(commonest).
Conjunctival Granuloma.
Iris Granuloma.
Optic neuritis.
Chorioretinitis.
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Ocular Sarcoidosis
Iris GranulomaIris Granuloma
Conjunctival GranulomaConjunctival Granuloma
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Anterior Anterior UveitisUveitis
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URT & Oral Cavity Sarcoidosis
Sinusitis.
Nasal congestion.
Intermittent epistaxis.
Destruction of nasal septum & Saddle Nose.
Upper airway obstruction, stridor & acute
respiratory failure.
Hoarseness.
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URT & Oral Cavity Sarcoidosis
Saddle NoseSaddle Nose
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Exocrine Glands
Panda SignPanda Sign
Bilateral symmetrical gallium uptake by the lacrimal, parotid,
and submandibular glands with Sicca syndrome
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Exocrine Glands
Heerfordt SyndromeHeerfordt Syndrome
Bilateral hilar lymphadenopathy.
Fever.
Facial palsy.
Parotid enlargement.
Uveitis.
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Joint & Musculoskeletal Sarcoidosis
Phalanges in the hands & feet are most frequently
affected.
Multiple.
Punched out lytic lesions, lacelike honeycomb
appearance, or extensive bone erosion with
pathologic fractures.
The articular spaces are usually intact
Arthralgia & polyarthritis.
Subcutaneous soft-tissue mass or tenosynovitis.
Myopathy.
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Skeletal Sarcoidosis
PUNCHED OUT LYTIC LESIONS PUNCHED OUT LYTIC LESIONS Focal osteolytic lesions in the fingers are Focal osteolytic lesions in the fingers are
most common abnormality.most common abnormality.
LACY TRABECULAR PATTERNLACY TRABECULAR PATTERN Osteolysis has left a lacy trabecular Osteolysis has left a lacy trabecular
pattern in this phalanx (arrow)pattern in this phalanx (arrow)
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Muscle Sarcoidosis
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Endocrine Sarcoidosis
Involvement of the
hypothalamus Diabetes
Insipidus
Hyperintensity of the
posterior pituitary lobe
caused by intracellular
nerosecretory granules.
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Vitamin D in Sarcoidosis
Extrarenal source of calcitriol in Sarcoidosis is
Alveolar Macrophage & Epithelioid cells that
contains 1,α-hydroxylase, which converts 25(OH)
D3 to 1,25(OH)2 D3.
PTH gene expression is up-regulated by TNF-α &
IL-6 produced by sarcoid macrophages.
Absence of feedback for hypercalcemia no
down-regulation of 1,α-hydroxylase in response to
high level of calcitriol & PTH.
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Renal Sarcoidosis
Calcium metabolism in Calcium metabolism in Sarcoidosis First described by Harrel in 1939
Clinical manifestations:
- Hypercalciuria 40-62% (>400 mg/24hr)
- Hypercalcemia – asymptomatic, 5%
- Nephrocalcinosis from chronic hypercalciuria +/- hypercalcemia
- Nephrolithiais 10%
- Main cause of chronic renal failure
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Renal Sarcoidosis
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Neurosarcoidosis
Unilateral or bilateral
Bell’s palsy.
Optic neuritis.
Multiple or solitary
parenchymal mass.
May have a ring-like
appearance.
Mimic glioblastoma or
metastases.
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Neurosarcoidosis
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Hematologic Sarcoidosis
Lymphadenopathy: cervical, axillary,
epitrochlear & supraclavicular.
Splenomegly & hypersplenism.
Peripheral blood lymphopenia.
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Hepatic Sarcoidosis
Dysfunction of these organ is
uncommon.
Hepatosplenic Sarcodosis: minimal
organomegaly & coalescing granulomas.
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Liver & Spleen Sarcoidosis
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GIT Sarcoidosis
Most common site: stomach dyspepsia
& abdominal pain.
Gastric sarcoidosis has predilection for the
antrum.
Diagnosis requires endoscopic biopsy
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Genital Sarcoidosis
Testicular involvement can be associated with Epididymitis and is typically Bilateral & Multiple.
Does not affect fertility & does not increase the incidence of fetal or obsterical complications.
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Cardiac Sarcoidosis
Clinically evident cardiac sarcoidosis is uncommon, Clinically evident cardiac sarcoidosis is uncommon, affecting 2-7% of patients with sarcoidosis. However, affecting 2-7% of patients with sarcoidosis. However, occult involvement is much higher (> 20%).occult involvement is much higher (> 20%).
Cardiac involvement may occur at any point during Cardiac involvement may occur at any point during the course of sarcoidosis, may occur in the absence the course of sarcoidosis, may occur in the absence of pulmonary or systemic involvement & may be a of pulmonary or systemic involvement & may be a presenting feature.presenting feature.
Sarcoidosis can involve any part of the heart, Sarcoidosis can involve any part of the heart, including myocardium, endocardium & pericardium.including myocardium, endocardium & pericardium.
Although the disease is often clinically silent, cardiac Although the disease is often clinically silent, cardiac sarcoidosis is a leading cause of death among sarcoidosis is a leading cause of death among patients with sarcoidosis, with mortality rate of 50-patients with sarcoidosis, with mortality rate of 50-85%.85%.
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Clinical Manifestations of Cardiac Sarcoidosis
Asymptomatic granulomata.
Conduction defects (e.g., bundle branch blocks; complete heart block).
Atrial arrhythmias.
Mitral insufficiency.
Ventricular aneurysms.
Pericardial effusions; fibrosis.
Tachyarrhythmias (ventricular > atrial).
Congestive heart failure.
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Cardiac Sarcoidosis
Guidelines for Diagnosis of Cardiac Sarcoidosis from Japanese Ministry of Health & Welfare:
Cardiac sarcoidosis is diagnosed when histologic analysis of operative or endomyocardial biopsy specimens demonstrates epithelioid granuloma without caseating granuloma
Clinical diagnosis group:
In patients with histologic diagnosis of extracardiac sarcoidosis, cardiac sarcoidosis is diagnosed when (a) and 1 or more of (b–e) are present.
(a) Complete right bundle branch block, left-axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contraction (>grade 2 in Lown’s classification), or abnormal Q or ST–T change on electrocardiogram or Holter electrocardiogram
(b) Abnormal wall motion, regional wall thinning or thickening, or dilatation of LV on echocardiogram
(c) Perfusion defect in 201Tl myocardial scintigram or abnormal accumulation in 67Ga-citrate or 99mTc-pyrophosphate myocardial scintigram
(d) Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed ejection fraction of LV
(e) Interstitial fibrosis or cellular infiltration over moderate grade in endomyocardial biopsy even if findings are nonspecific
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Diagnosis
Clinical.
Radiological (Chest radiograph & Gallium scan).
Functional (Spirometry, DLCO & Lung Volumes).
Laboratory (CBC with differential count & SACE).
Skin tests.
Biopsy.
ECG.
Opthalmological examination.
Organ-specific investigations.
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Radiological Staging of Sarcoidosis
Scadding's
Classification
Stage 0=normal
Stage 1=Hilar LDN alone
Stage 2=Hilar
LDN+parenchymal
infiltrates
Stage 3=Parenchymal infiltrates
alone
Stage 4=Pulmonary fibrosis
Strong predilection for the Strong predilection for the
Upper LungUpper Lung
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Gallium 67 Scan
Lung gallium scan is a type of nuclear scan involving radioactive gallium (Ga.).
The test helps determine whether a patient has inflammation in the lungs.
Gallium is injected IV.
The scan will be taken 6-24 hrs after the gallium is injected. (time depends on whether the condition is acute or chronic ).
During the test, you lie on a table that moves underneath a scanner called a gamma camera. The camera detects the rays emitted by the gallium.
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Gallium 67 Scan
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Serum Angiotensin Converting Enzyme (SACE)
SACE is the most widely used test in the follow-up of sarcoidosis patients.
It is a membrane bound glycoprotein found in Activated Alveolar Macrophages & at the surface of Epithelioid cells & consequently may reflect development & extent of granulomas.
It may be normal in early & acute disease reflecting the small number of granulomas present at this stage.
It is poorly correlated with pulmonary function & variably related with radiographic stage.
It correlates with the degree of extrapulmonary lesions.
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Serum Angiotensin Converting Enzyme (SACE)
ACE is secreted by granulomas and may be present in serum, CSF & BAL washings.
Steroids decrease SACE with a delay after onset of treatment. A minimum dose of prednisone is required to normalized SACE. After discontinuing steroids, a transient increase in SACE may occur before final normalization.
In spontaneous recovery of sarcoidosis without steroids, even previously persistently elevated SACE levels may normalize.
It is positive in 60% of sarcoidosis patients. SACE is neither sensitive nor specific in
diagnosing sarcoidosis.
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Causes of Positive ACE
Sarcoidosis Pulmonary Berylliosis Asbestosis
Gaucher's Disease Hypersensitivity Pneumonitis Miliary Tuberculosis Coccidioidomycosis Lymphoma Silicosis
Non-Pulmonary Primary Biliary Cirrhosis Diabetes Mellitus Leprosy Crohn's Disease Hyperthyroidism .
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The Kveim-Siltzbach Test
The test is based upon studies conducted by Dr. Morten
Ansgar Kveim, a Norwegian dermatologist in 1941 & was
later studied by Dr. Louis Siltzbach in New York.
It is the only test that, if positive, is considered to be
diagnostic of sarcoidosis.
It is both sensitive & specific.
The test involves intradermal injection of a suspension of
granuloma-containing spleen or lymph node from a patient
with sarcoidosis.
A positive test is characterized by the formation of a papule
at the site of injection within 4-6 wks which, on microscopic
examination, exhibits non-necrotizing granulomas.
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The Kveim-Siltzbach Test
Because of the difficulties involved in preparation,
standardization & validation of the test material as
well as significant variation in the sensitivity &
specificity of test suspensions obtained from
different sources, the need for a biopsy procedure
& the wait of 4-6 weeks for a diagnosis, the Kveim
test has been largely replaced by TBLB for the
diagnosis of sarcoidosis.
It may have a role in atypical cases where tissue is
difficult or impossible to obtain, such as in
neurosarcoidosis.
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The Kveim-Siltzbach Test
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Lung Volumes & Capacities
Obstructive impairment is as common as restrictive impairment
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DLCO
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Biopsy
Palpable lymph nodes
Subcutaneous nodule
Cutaneous lesion
Enlarged parotid
Lacrimal gland
Transbronchial lung biopsy (TBLB)
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Cardiac Sarcoidosis
Diagnostic test Clinical feature
ECGNon-specific ST & T wave changes; conduction disturbances; arrhythmias
24-Holter monitor Arrhythmias (rest or exercise)
2-D echocardiography Focal hypokinesis; ventricular thinning or hypertrophy; wall motion abnormalities; depressed ejection fraction; papillary muscle dysfunction; bright echos
Adenosine thallium201 radionuclide scan
Segmental defects; improve with exercise or adenosine
Gallium67 & Technetium99 scans
Increased myocardial uptake
Positron emission tomography (PET)
Increased myocardial uptake
MRI High-intensity lesions; thinning ventricular wall
Endomyocardial biopsies Nonnecrotizing granulomata;
mononuclear cell infiltrates; fibrosis
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Treatment of Sarcoidosis
Corticosteroids: Glucocorticoids are very potent & effective drugs
in preventing & suppressing inflammation caused by mechanical, chemical, infectious & immunological stimuli.
They act mainly by repression of inflammatory genes, e.g. interleukin (IL)-1 & tumour necrosis factor (TNF), adhesion molecules & receptors & partly by induction of anti-inflammatory genes e.g.,IL-1 receptor antagonist.
In Sarcoidosis, corticosteroids have been shown to restore the balance between locally produced type-1 & type-2 T-helper cell cytokines.
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When To Treat?
Progressive or persistent symptomatic pulmonary disease
Threatened organ failure e.g., severe cardiac, neurological.
Asymptomatic pulmonary disease with persistent infiltrates
or progressive loss of lung function
Palpable splenomegly or hypersplenism
Severe myopathy, fatigue & weight loss.
Disfiguring skin lesion.
Uveitis unresponsive to topical corticosteroids.
Persistent hypercalcaemia, renal or hepatic dysfunction.
Painful lymphadenopathy.
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Treatment of Sarcoidosis
Decision to Treat with CORTICOSTEROIDS:
Patient Subgroup Decision:
1. Asymptomatic Pts → No treatment
2. Mild Pulmonary Dysfunction → Observation
3. Mild-Mod. Pulmonary Dysfunction → Observation →
Treat if no improvement after 6 months.
4. Severe Pulmonary Dysfunction → Treatment
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Corticosteroids in Systemic Sarcoidosis
DrugDrug DoseDose
CorticosteroidsCorticosteroids
Prednisone 20-40 mg/d for 2 wk, 5 mg/2 wks till Prednisone 20-40 mg/d for 2 wk, 5 mg/2 wks till 10-15 mg, then maintain for 8-12 ms, then taper 10-15 mg, then maintain for 8-12 ms, then taper 2.5 mg/2-4 wks.2.5 mg/2-4 wks.
Reinstitute if relapse Reinstitute if relapse
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Alternative Drug Therapy
Methotrexate 10-20 mg/wk + folate 1 mg/d
Hydroxychloroquine 200 mg once or twice/day
Chloroquine 500 mg/other day for 6 ms then 6 ms drug holiday
Azathioprine 100-200 mg/day
Doxycyclin, Minocyclin 100 mg twice/day
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Alternative Drug Therapy
Corticosteroid resistance, however, has also
been described in Sarcoidosis patients & is
characterised by exaggerated TNF-release by
alveolar macrophages compared to that found
in patients showing favourable responses to
steroids.
Thus, steroid-refractory disease might benefit
from treatment with anti-TNF-antibody, i.e.
infliximab.
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Alternative Drug Therapy
Infliximab & Etanercept: Infliximab is a “monoclonal antibody” that
blocks the action of TNFα by binding to it & preventing it from signaling the receptors for TNFα on the surface of cells.
TNFα is one of the key cytokines that triggers & sustains the inflammation response.
Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble & transmembrane forms of TNFα & inhibits or prevents the effective binding of TNFα with its receptors.
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Alternative Drug Therapy
Infliximab & Etanercept: Treatment with infliximab has recently proved
effective in the treatment of refractory sarcoidosis.
Etanercept, a soluble TNF receptor construct, was found ineffective against pulmonary & chronic ocular sarcoidosis.
Etanercept binds soluble TNF alone, whereas infliximab also binds to the membrane-bound form.
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Potential Role for Antioxidants in Sarcoidosis
Enhanced production of reactive oxygen species
(ROS), capable of reducing endogenous defense
levels & enhancing inflammation, is suggested to
play a role in sarcoidosis.
Antioxidant supplementation offers protection not
only against ROS-mediated damage but also by
reducing inflammation.
A promising candidate for antioxidant
supplementation is the flavonoid quercetin.
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Recommended Clinical Evaluation In Sarcoidosis
Baseline:•History taking, with emphasis on occupational & environmental exposure•Physical examination, with emphasis on lung, skin, eye, liver, heart•Biopsy to obtain histologic confirmation of non-caseating granulomas•Chest radiography•Pulmonary-function testing — spirometry + measurement of gas exchange (e.g., DLCO (or) ABGs)•Electrocardiography•Ophthalmologic evaluation with slit-lamp examination•Biochemical evaluation for hepatic & renal function+ measurement of s. Ca•Tuberculin skin test•Other tests depending on clinical presentation & suspicion of extrathoracic disease; assessment of extent and severity of organ involvement
Follow-up:•Monitoring for resolution or disease progression & for new organ involvement.•Referral to subspecialists if there is evidence of disease progression or new organ involvement.
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Take Home Messages
Therapy need not be given to all patients. Once initiated, at least 1 yr of treatment is required. Monitoring is mandatory if steriods discontinued. Steroid sparing agents useful for chronic patients. No long term benefit from corticosteroid therapy in
asymptomatic pts., regardless of CXR stage. Asymptomatic pts. with normal PFT should not be
treated because of radiographic abnormality alone. Neurologic, cardiac & ocular involvement warrants
early therapy.
Orphan Lung Orphan Lung
DiseasesDiseases
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Definition
An ‘Orphan' disease is the name given
to a disease that is not widely
researched and/or for which there is no
specific treatment, thus making patients
feel 'orphan' in the world of healthcare.
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Orphan Lung Diseases
Lymphangioleiomyomatosis (LAM).
Pulmonary Langerhans’ Cell histiocytosis.
Pulmonary Alveolar Proteinosis (PAP).
Amyloidosis.
Scleroderma.
Idiopathic chronic eosinophilic pneumonia.
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Lymphangioleiomyomatosi
s
Lymphangioleiomyomatosis (LAM) is a rare
disorder of unknown etiology characterized by
proliferation of atypical smooth muscle cell (LAM
cell) in pulmonary lymphatics, venules & small
airways.
The dominant clinical features are: ILD, chylous
pleural effusion & recurrent pneumothorax.
It occurs in females during the childbearing
period.
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Diagnosis of LAM
Clinical.
Radiological: chest radiograph.
PFTs (combined obstructive & restrictive).
Biopsy: TBLB.
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Treatment of LAM
Hormonal therapy e.g., progesterone &
tamoxifen.
Hormonal manipulations e.g.,
oophorectomy.
Lung transplantation.
New experimental therapies e.g.,
Rapamycin, Doxycycline & Octreotide.
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Pulmonary Langerhans’ Cell
Histiocytosis
Langerhans’ cell histiocytosis or Eosinophilic
granuloma of the lung.
Clinical: dry cough, dyspnea, chest pain rhinitis,
fatigue, fever, pneumothorax, hemoptysis, diabetes
insipidus & skeletal involvement with cystic bony
lesions .
Examination: clubbing, cor pulmonale & crackles.
Langerhans’ cells are differentiated cells of
monocyte–macrophage lineage that function as
APCs.
Common in young smokers.
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Diagnosis of Langerhans’ Cell
Histiocytosis
Clinical.
Radiological: chest radiograph.
PFTs (normal, obstructive, restrictive or
mixed).
Biopsy: BAL & TBLB.
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Diagnosis of Langerhans’ Cell
Histiocytosis
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Diagnosis of Langerhans’ Cell
Histiocytosis
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Corticosteroids & cytotoxic drugs no
value.
New experimental therapies e.g., gene
therapy.
Treatment of Langerhans’ Cell
Histiocytosis
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Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a
syndrome of unknown etiology characterized by
excessive accumulation of surfactant
phospholipids & apoproteins within alveolar
spaces.
It can be primary (classic) or secondary
(pseudoproteinosis) due to environmental
exposure, drugs, infections & hematologic
malignancies.
More common in males between 30 & 50 yrs.
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Diagnosis of PAP
Clinical: dyspnea, dry cough, clubbing,
cyanosis & widespread crackles.
Radiological: chest radiograph.
PFTs restrictive pattern.
ABGs.
Laboratory LDH.
Biopsy: FOB, BAL, TBLB & open lung
biopsy lipid laden
macrophages.
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Diagnosis of PAP
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Diagnosis of PAP
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Treatment of PAP
Therapeutic whole lung lavage under
general anesthesia using double lumen
ETT (10-20 L saline for every lung).
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